Stress-induced ovarian dysfunction and associated hypoestrogenism is common in women and can have a negative impact on health. Termed functional hypothalamic chronic anovulation (FHCA), this syndrome is a reversible form of ovarian failure in which cognitive responses to life events activate central neural circuits that disrupt gonadotropin releasing hormone (GnRH) secretion. Since women with FHCA are hypercortisolemic, this anovulation may result from increased release of corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) produced by a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. However, it is not clear how behavioral events produce this dysregulation, how the dysregulation is sustained, and how excess CRH and/or AVP inhibit gonadotropin secretion. Also, genetic factors may be important as individuals with a short variant polymorphism in the gene encoding the serotonin reuptake transporter, SERT, are more susceptible to stress. Like women with FHCA, socially subordinate female rhesus monkeys living in stable groups show HPA dysregulation and sustained periods of gonadotropin deficiency. Using this animal model, the project will determine the neuroendocrine and molecular mechanisms by which social stress inhibits GnRH. Specific Aim 1 will test the hypothesis that estradiol potentiates stress-induced increases in CRH and AVP by decreasing glucocorticoid negative feedback and this is enhanced in females with the short variant in the SERT gene. This aim will also test the hypothesis that hypoleptinemia, characteristic of subordinate females, acts to sustain this HPA dysregulation. Using specific CRH and AVP receptor antagonists as well as infusions of CRH and/or AVP, Aim 2 will test the hypothesis that gonadotropin secretion is diminished in subordinate females by a CRH - AVP synergistic inhibition. Aim 3 will test the hypothesis that the estradiol-induced CRH - AVP synergistic inhibition of gonadotropin secretion in subordinate females is mediated through an opioid pathway and the inhibition of hypothalamic GnRH expression. This project will clarify the neuroendocrine mechanisms mediating socially-induced gonadotropin deficiency and will thus enhance the ability of health providers to diagnose and treat FHCA in women.